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Parkinson Disease, Late-Onset

- Cell Therapy Approaches

Parkinson's disease (PD) is a progressive neurodegenerative disease with clinical symptoms of muscle rigidity, tremor, bradykinesia and postural instability. These motor deficits are the consequence of a symptomatic loss of dopaminergic neurons (DA) in the substantia nigra pars compacta (SNpc) and their terminals in the striatum. The symptoms become more pronounced as the disease progresses, due to the continuous degeneration of dopaminergic neurons. PD is commonly treated by administration of Levodopa to elevate the levels of dopamine, in compensation for the lost DA neurons. A parallel cell therapy approach is transplantation of stem cell-derived dopaminergic neurons to serve as a stable source for dopamine secretion. In addition, stem cells are being used to promote neuroprotection, in efforts to attenuate destruction of DA neurons.

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Cell Therapy Approaches

The first clinical trial of cell transplantation therapy for PD patients utilized aborted human fetal ventral midbrain tissue. Although some grafted patients have exhibited dramatic improvements in their symptoms, due to ethical issues in using aborted fetal tissues, researchers have developed alternative adult stem cell-based therapies. Current cell therapies for PD focus on the use of mesenchymal stem cells (MSCs) to promote neural protection and regeneration of DA neurons, and on the use of human embryonic stem cells (hESC) and induced pluripotent stem cells (iPSC)-derived neurons to replace the lost neurons.

Embryonic stem cells (ESCs) are highly proliferative and can be differentiated into dopaminergic precursor cells and neurons. Rodent and human ESC-derived dopaminergic neurons have been shown to generate some degree of functional recovery after transplantation into the striatum of PD rats. However, studies have shown that the survival of ESC-derived DA neurons post-transplantation is relatively low. A major concern with use of ESC-derived neurons for transplantation in PD patients is the risk of adverse effects, such as tumor formation, which has been reported in rats.

Induced pluripotent stem cells (iPSC) can be derived from the patient's own cells and differentiated into DA neurons and precursor cells in-vitro. The ability to generate neurons from the PD patient's own cells reduces the risk of immune rejection, but the risk from tumor formation due to inadequate differentiation processes, is still high. Currently, DA neurons-derived from patient iPSC, are being used as a cellular model of PD, to learn about disease-related molecular mechanisms and for drug screening.

Mesenchymal stem cells (MSCs) can be easily isolated and expanded in-vitro. They have immunomodulatory and anti-inflammatory properties, possess some differentiation capacity, and most important, are not burdened with the ethical issues associated with embryonic stem cells and stem cells of fetal origin.

Bone marrow-derived MSCs (BM-MSCs) have the capacity to protect and regenerate damaged DA neurons, as shown in several PD animal models. Moreover, behavioral recovery was also demonstrated after BM-MSC transplantation in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Similarly, BM-MSC-derived neurons expressed tyrosine hydroxylase (TH) and promoted behavioral recovery after transplantation in a 6-OHDA mouse model of PD.

Current PD-related clinical trials focus on the use of MSCs, derived either from the patient or from donors, to promote neural protection and regeneration of DA neurons. For example, a phase 1/phase 2 clinical trial utilizing BM-MSCs is being conducted at the Guangzhou General Hospital.